PROJECT SUMMARY/ABSTRACT Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the general population. AD is associated with defective skin barrier function, microbial dysbiosis, as well as various cutaneous immune abnormalities including type 2 inflammation and decreased cutaneous host defense. These abnormalities translate into multiple phenotypes and endotypes that are not fully defined and therefore, effective targeted therapies, beyond type 2 immune blockade, to reverse these various subsets of AD are lacking. Beyond its effects on cutaneous defense, AD is associated with systemic inflammation and appears to be the first step in the development of other atopic conditions including food allergy and asthma. This grant application is being submitted in response to RFA-AI-19-014, Atopic Dermatitis Research Network-Leadership Center (ADRN-LC). The goal of this proposal is to create an ADRN-LC which will provide the overall scientific strategy and organizational structure to the ADRN and will interact closely with the ADRN Clinical Research Centers (ADRN-CRCs), to support the conduct of multi-site clinical studies and trials that will elucidate mechanisms of skin barrier dysfunction and cutaneous immune responses in atopic dermatitis (AD). The central hypothesis in this application is that different phenotypes and endotypes of AD are associated with distinct defects in their skin barrier, microbiome, and skin immune responses which can be characterized by novel approaches to skin sampling and open up avenues for paradigm shifting therapeutic interventions to benefit patients with severe persistent AD. We will achieve our objectives with the following Aims: Specific Aim 1: To establish an Administrative and Clinical Research Operations Leadership Center that will be responsible for implementation, coordination, and funding of clinical trials and studies for the ADRN-LC in research areas evaluating mechanism and treatment of AD. Specific Aim 2: To develop a Network-wide multi-center ADRN clinical trial to evaluate the long- term effects of targeted microbiome transplantation on clinical outcomes in AD as well as epithelial barrier function, microbial dysbiosis, and cutaneous immunity. Specific Aim 3: To design a Network-wide ADRN one-year observational study to assess the stability of AD phenotypes/endotypes using a Network correlation analysis of transcriptomics (conventional and single cell RNA sequencing), skin tape proteomics, lipidomics, and microbiome over time in subjects with persistent mild vs. persistent severe AD and assessment of therapeutic responses to topical corticosteroids and Dupilumab. Specific Aim 4: To carry out a Network-wide multi-center ADRN clinical trial to examine the effects of targeted IL-1 blockade on the clinical outcome, skin microbiome, epithelial skin barrier, and cutaneous immune response in AD patients who have an inadequate response to IL-4/IL-13 blockade using Dupilumab therapy. Accomplishment of these Specific Aims will contribute to novel and important advances in our understanding of mechanisms of host skin defense and paradigm-shifting treatments of AD. The establishment of this ADRN-LC will also provide budgetary and scientific resources for the Systems Biology of Early Atopy Birth Cohort study that is under development by the Consortium for Food Allergy Research (CoFAR).